General Information

Linzess (linaclotide) is a guanylate cyclase-C (GC-C) agonist. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, resulting in increased intestinal fluid and accelerated transit.

Linzess is specifically indicated for the treatment of adults with irritable bowel syndrome with constipation and for adults with chronic idiopathic constipation.

Linzess is supplied as a tablet for oral administration. The recommended dose of Linzess for irritable bowel syndrome with constipation is 290 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day. The recommended dose of Linzess for chronic idiopathic constipation is 145 mcg taken orally once daily on an empty stomach, at least 30 minutes prior to the first meal of the day.

Clinical Results

FDA Approval

The FDA approval of Linzess for irritable bowel syndrome with constipation was based on two double-blind, placebo-controlled, randomized, multicenter trials, Trial 1 (n=800) and Trial 2 (n=804). All subjects met the Rome II criteria for IBS. The subjects received Linzess 290 mcg or placebo. The trial designs were identical through the first 12 weeks, and thereafter differed only in that Trial 1 included a 4-week randomized withdrawal (RW) period, and Trial 2 continued for 14 additional weeks (total of 26 weeks) of double-blind treatment. During the trials, subjects were allowed to continue stable doses of bulk laxatives or stool softeners. The four primary efficacy responder endpoints were based on a patient being a weekly responder for either at least 9 out of the first 12 weeks of treatment or at least 6 out of the first 12 weeks of treatment:For the 9 out of 12 weeks combined primary responder endpoint, a subject had to have at least a 30% reduction from baseline in mean abdominal pain, at least three complete spontaneous bowel movements (CSBMs) and an increase of at least one CSBM from baseline, all in the same week, for at least 9 out of the first 12 weeks of treatment. Each of the two components of the 9 out of 12 weeks combined responder endpoint, abdominal pain and CSBMs, was also a primary endpoint.For the 6 out of 12 weeks combined primary responder endpoint, a subject had to have at least a 30% reduction from baseline in mean abdominal pain and an increase of at least one CSBM from baseline, all in the same week, for at least 6 out of the first 12 weeks of treatment. To be considered a responder for this analysis, subjects did not have to have at least three CSBMs per week.In both trials, the proportion of subjects who were responders to Linzess 290 mcg was statistically significantly higher than with placebo.Efficacy Responder Rates: at Least 9 Out of 12 Weeks:Trial 1 combined responder endpoint: Linzess: 12.1% responders vs. placebo: 5.1% responders. Trial 2 combined responder endpoint: Linzess: 12.7% responders vs. placebo: 3.0% responders.Efficacy Responder Rates: at Least 6 Out of 12 Weeks:Trial 1 combined responder endpoint: Linzess: 33.6% responders vs. placebo: 21.0% responders. Trial 2 combined responder endpoint: Linzess: 33.7% responders vs. placebo: 13.9% responders.In both trials improvement from baseline in abdominal pain and CSBM frequency was seen over the first 12-weeks of the treatment period. For change from baseline in the 11-point abdominal pain scale, Linzess 290 mcg began to separate from placebo in the first week. Maximum effects were seen at weeks 6 - 9 and were maintained until the end of the study. The mean treatment difference from placebo at week 12 was a decrease in pain score of approximately 1.0 point in both trials (using an 11-point scale). Maximum effect on CSBM frequency occurred within the first week, and for change from baseline in CSBM frequency at week 12, the difference between placebo and Linzess was approximately 1.5 CSBMs per week in both trials. During the 4-week randomized withdrawal period in Trial 1, subjects who received Linzess during the 12-week treatment period were re-randomized to receive placebo or continue treatment on Linzess 290 mcg. In the Linzess-treated arm re-randomized to placebo, CSBM frequency and abdominal-pain severity returned toward baseline within 1 week and did not result in worsening compared to baseline. Subjects who continued on Linzess maintained their response to therapy over the additional 4 weeks. Subjects on placebo who were allocated to Linzess had an increase in CSBM frequency and abdominal pain levels that were similar to the levels observed in patients taking Linzess during the treatment period.

The FDA approval of Linzess for the treatment of chronic idiopathic constipation was based on two double-blind, placebo-controlled, randomized, multicenter clinical trials, Trial 3 (n=642) and Trial 4 (n=630). All subjects met modified Rome II criteria for functional constipation. The subjects received Linzess 145 mcg, 290 mcg, or placebo once daily. The trial designs were identical through the first 12 weeks. Trial 3 also included an additional 4-week randomized withdrawal (RW) period. During the trials, subjects were allowed to continue stable doses of bulk laxatives or stool softeners. Efficacy of Linzess was assessed using overall responder analysis and change-from-baseline endpoints. A CSBM overall responder in the CIC trials was defined as a subject who had at least three CSBMs and an increase of at least one CSBM from baseline in a given week for at least 9 weeks out of the 12-week treatment period. In Trials 3 and 4, the proportion of subjects who were CSBM responders was statistically significantly greater with the Linzess 145 mcg dose than with placebo. Linzess 290 mcg did not consistently offer additional clinically meaningful treatment benefit over placebo than that observed with the 145 mcg dose. The following data is for the approved 145 mcg dose of Linzess:CSBM Overall Responder at Least 9 Out of 12 Weeks:Trial 3: Linzess 145 mcg: 20.3% responders vs. placebo 3.3% responders. Trial 4: Linzess 145 mcg: 15.5% responders vs. placebo 5.6% responders.In both trials CSBM frequency reached maximum level during week 1 and was also demonstrated over the remainder of the 12-week treatment period. For the mean change from baseline in CSBM frequency at week 12, the difference between placebo and Linzess was approximately 1.5 CSBMs. In both trials, Linzess also resulted in significantly greater improvements compared with placebo in stool frequency and stool consistency. During the 4-week randomized withdrawal period in Trial 3, subjects who received Linzess during the 12-week treatment period were re-randomized to receive placebo or continue treatment on the same dose of Linzess taken during the treatment period. In Linzess-treated patients re-randomized to placebo, CSBM and SBM frequency returned toward baseline within 1 week and did not result in worsening compared to baseline. Subjects who continued on Linzess maintained their response to therapy over the additional four weeks. Subjects on placebo who were allocated to Linzess had an increase in CSBM and SBM frequency similar to the levels observed in subjects taking Linzess during the treatment period.

Side Effects

Adverse reactions associated with the use of Linzess may include, but are not limited to, the following:

diarrhea

abdominal pain

flatulence

abdominal distension

Mechanism of Action

Linzess (linaclotide) is a guanylate cyclase-C (GC-C) agonist. Both linaclotide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation in intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit.